Neoadjuvant Chemotherapy and Adjuvant Chemoradiotherapy in the
Treatment of Gastric Adenocarcinomas
By
James H. Feldman, PA-S
A Capstone Paper submitted to the faculty of
the University of North Carolina at Chapel Hill
in partial fulfillment of the requirements
for the degree of Master of Science
in the Physician Assistant Program
Chapel Hill
November 28, 2018
___
Kim Faurot PhD _____________________________
Name and title of First Reader
______________________
Date
Amanda Corbett PharmD____________________
Name and title of Second Reader
______________________
Abstract
Purpose: Gastric cancer is the third leading cause of cancer-related death worldwide. From 1974-1975, patients who received gastric resection only had a 5-year survival rate of 15.3%.16 With the introduction
of chemoradiotherapy, the 5-year survival rate increased to 23.2% from 1995-2001.16 One question
which can be imposed is how necessary is neoadjuvant chemotherapy in addition to surgery compared to surgery then adjuvant chemoradiotherapy in improvement of 5-year survivability of a gastric adenocarcinoma.1
Methods and Materials: 7 random control trials using neoadjuvant chemotherapy and 2 random control trials using adjuvant chemoradiotherapy were examined using a network meta-analysis to determine which was the more beneficial for 3-year, 5-year, and Overall Survival. Secondary outcome was to determine which caused more life-altering side effects
Results: There was no statistical benefit found in the use of adjuvant chemoradiotherapy over the use of neoadjuvant chemotherapy. The 5-year and Overall mortality were consistently higher in the adjuvant chemoradiotherapy group, but the strength of data in the network meta-analysis was inconclusive. Conclusion: Further study the use of neoadjuvant chemotherapy plus surgery in the treatment of gastric adenocarcinomas in order to improve quality of life for the patients is recommended as well as further study of adjuvant chemoradiotherapy to improve survivability.
Neoadjuvant Chemotherapy and Adjuvant Chemoradiotherapy in the Treatment of Gastric Adenocarcinomas
Introduction
Epidemiology
Gastric cancer is the third leading cause of cancer-related death worldwide.1 From a global perspective,
gastric cancer is the 4th most common cancer to be diagnosed among men and 5th most common among
women. Developing countries have a higher incidence of gastric cancer and account for 70% of
diagnosed cases. These countries also have a mortality rate 5-10% greater than developed countries like the United States. This is most likely due to inadequate access to the more contemporary treatments, such as neoadjuvant chemotherapy or adjuvant chemoradiotherapy2. Overall, the mortality of gastric
cancer is declining.
There are a variety of risk factors which may increase the incidence of an adenocarcinoma (Appendix A). Environmental factors are believed to play one of the largest roles in the increase and decrease of gastric cancer. Dietary salt intake is associated with higher incidence and mortality.3 Light to
moderate alcohol consumption poses a slight increase in risk for the development of gastric cancer, whereas heavy alcohol consumption (>4 drinks per day or 60g of alcohol per day) has a proven
significant increase in the risk of development.4 Similar to most other cancers, tobacco use also plays a
role; there is strong data which show an association between duration of cigarette use and the
likelihood of development of gastric cancer.5 Fruits and vegetables are observed to be protective against
gastric cancer. Two to five servings of fruits and vegetable per day has a proven positive impact; in fact, people who consume recommended amounts of fruits and vegetables over a 40-year period have almost a 30% less risk of gastric cancer.6,7 Increased vitamin C consumption has also been linked as
H. pylori bacteria is difficult.6 Although these factors can increase the risk of development of gastric
cancer, it can also be caused by an infectious etiology.
There are two known infectious causes of an increase in risk of the development of gastric cancer: H. pylori and Epstein-Barr virus (EBV). H.pylori is considered a class I carcinogen by the World Health Organization (WHO) for the development of cancer. There is an approximate 3% greater chance of developing a gastric adenocarcinoma after the development of an H. pylori infection.8 Additional risk
is attributed to H. pylori because the same environmental factors which influence a gastric
adenocarcinoma (increase the risk- high salt intake, cigarette use, alcohol consumption; decrease the risk- consumption of fruits and vegetables, increase in dietary Vitamin C) influence the effect of H. pylori
in the same way, respectively.8 The specific mechanism of action of how the Epstein-Barr Virus affects
gastric adenocarcinomas is unknown, but there is a correlation with the presence of the virus and those affected by gastric cancer; approximately 8% of gastric cancer are EBV carcinomas.9
There is also a genetic component which increases the risk of gastric cancer. A germline mutation of the CDH1 gene located on chromosome 16q22 carries an increase risk in the early development of gastric adenocarcinomas.10 Gastric cancer has also been linked to Lynch Syndrome
families carrying the germline mutations MLH1 and MSH2.11
Pathophysiology
Gastric cancer should not be recognized as a single disease, but rather a collection of individual diseases within a single organ. Since 1965, Lauren’s criteria is the most widely accepted and frequently used classification system of gastric cancer.12 Historically, the Lauren subtype system breaks down
intestinal metaplasia, and finally dysplasia. This type of gastric cancer affects males to females in the US at a 3:1 ratio, with Caucasians making up almost 60% of all patients.2 (what proportion of the gastric
cancers fall into each of these subtypes?)
Diffuse gastric cancer is described as widespread thickening and rigidity of the gastric wall.10,13
This type of cancer has no known precursor lesion and no association with chronic inflammation. Instead there is either a mutation or epigenetic silencing of the E-cadherin gene; CDH1 gene. E-cadherin is protein which mediates cell interactions and cell polarity by attaching to the cytoskeleton during mitosis. Without this protein, gastric cancer cells are able to dissociate from their matrix and metastasize.
Proximal gastric cancer effects the distal 1/3rd of the esophagus, the gastroesophageal junction,
and the gastric cardia. It is commonly caused by gastroesophageal reflux disease (GERD) and has been linked to Barrett’s Esophagus. H. pylori infections tend to be protective of this type of cancer. The H. pylori infection reduces acid production and decreases the GERD’s effect. Originally this subtype of gastric cancer was grouped with non-cardia intestinal gastric cancer because of the presentation: chronic inflammation, then intestinal metaplasia, and finally dysplasia. Due to its reversed interaction with H. pylori, proximal gastric cancer has become its own subtype.2
Approximately 10% of cancer-related deaths worldwide are linked to gastric cancer which has a high fatality to case ratio of 70%.2 Ove the last 30 years, the 5-year-survivablitily of gastric cancer has
increased from approximately 10% to over 20%.14 This increase is most likely due to improvements in
50%, other chemotherapies began to be tested. Epirubicin, cisplatin, and continuous infusion of 5-fluorouracil were found to have a response rate of approximately 71% as a post-operative adjuvant.15
These successful treatments led to the belief that gastric adenocarcinomas are chemotherapy sensitive tumors, so research started on different modalities and timings of infusions. In Japan, neoadjuvant chemotherapy research has gained interest in order to increase the number of patients who may be offered a curative resection. In the United States, the addition of postoperative chemoradiotherapy to gastric resections has proven to improve the 5-year survival rate. From 1974-1975, patients who received gastric resection only had a 5-year survival rate of 15.3%.16 With the introduction of
chemoradiotherapy, the 5-year survival rate increased to 23.2% from 1995-2001.16 One question which
can be imposed is how necessary is neoadjuvant chemotherapy in addition to surgery compared to surgery then adjuvant chemoradiotherapy in improvement of 5-year survivability of a gastric adenocarcinoma.2
Methods
Literature Search
A systematic literature search was done using the following databeases: Trip, Embase, Pubmed, CINAHL, and Google Scholar. The search terms used were “Gastric/stomach”,
“cancer/carcinoma/adenocarcinoma”, “neoadjuvant/preoperative chemotherapy”, “adjuvant Chemoradiotherapy/radiation/chemotherapy”, “surgery/surgery alone”, and “5 year survival”. The special database function “related articles” was used to maximize the search. The references from relevant articles and the randomized controlled trials used within the articles were searched to identify additional relevant articles. Due to the nature of the disease and the therapies provided, relevant data was acceptable from 2000 to current times. The records included 563 articles and after reviewed for duplicates, 552 articles remained. The articles’ title and abstracts were screened for relevance on the
topic and 37 remained. Of the 37 remaining articles, 11 studies were primarily used for the data in this report; 9 random controlled trials and a meta-analysis. The meta-analysis was chosen draw from the 7 random controlled trials (RCT) used in its research. Only research translated to/written in the English languae were applied and the last data search done on August 4, 2018.
Inclusion/Exclusion Criteria
The articles were screened using the following criteria: all articles were written or translated to English by the year 2000, all patients were diagnosed with gastric adenocarcinomas of the stomach or gastroesophageal junction which were histologically confirmed, resectable cancers only, no race or gender limitations, clear documentation of each intervention with procedure, only either preoperative chemotherapy or post operative chemotherapy with radiation were used in addition to a resection for the therapy groups, no chemotherapy or radiation were used with the control groups, no distant metasis were noted prior to randomization, the procedure must have complete resection of the carcinoma with margins <1cm, a response to each treatment was documented and the patients were categorized appropriately, and clear documentation of side effects from the medications were noted. Excluded articles with justification are listed in Appendix B.
Data Collection Process
All articles were examined by 1 author and then content and article relevance were reviewed by 2authors. This meta analysis is written in accordance to PRISMA guidelines, and the following data was extracted from each study: design from 10 RCTs, study population, and inclusion/exclusion criteria. Therapies of the studies were neoadjuvant chemotherapy (NAC) and adjuvant chemoradiotherapy (ACRT) listed in Table 317,18. No specific surgery was studied, as long as it met inclusion criteria. The
et al and Sung Kim et al in accordance with 1988 staging criteria of the American Joint Commission on Cancer18,20. Study population includes number of patients studied, race, age and gender.
Determination of Bias
Bias across this study was evaluated with the Cochrane Collaberation tool. High quality data was given a score of 4/5 or higher, medium quality data was given a score of 3/4, and low quality data was given a score of 2/4 or below. All studies will begin at 5 and will be deducted 1/2 of a point per qualified metric of bias. This will standardize the scoring system and assist in evaluation of quantified bias
evaluation. These scoring assignments were determined before the study began.
Results
Selected trials
Zero studies were identified which compared neoadjuvant chemotherapy to adjuvant chemoradiotherapy. The most appropriate way to compare the two therapies was determined to compare their effects versus a control (surgery alone) and then contrast the effectiveness of each therapy against each other using a network meta-analysis. The 9 RCTs evaluated began collecting data no later than 1991 and they were all published between 2000 and 2010, and they all followed patients for a minimum of 60 months each. Demographics and Therapies of each study are listed in Appendix C18,21–25. The main recorded demographic were T staging of the tumor, age range, and gender. Zhao et al.
and Kobayashi et al. did not include an initial T staging due to the studies concentrating on gene expression of PCNA, Fas/FasL and PD-ECGF. The flow diagrams in Appendix F show how each RCT’s participation was enacted18,21–25.
Primary Outcomes
The primary outcomes of the trials were to assess the 3-year survivability (Table 1&2), 5-year survivability (Table 3&4) and Overall Mortality (Table 5&6) of the therapies.17,21,23–27 There was
No study out of the NAC group showed any statistically significant improvement in 5-year mortality over surgery alone (RR 1.02, 95%CI 0.91, 1.15). Schuhmaker, Imano, and Wang studies generally favored NAC, but the strength of data was low. Nio and Kobayashi showed practically no difference in outcomes for NAC versus SA. Both studies out of the ACRT group showed a favorable 5-year survivability in the therapy groups, although the combined data proved to be not statistically significant (RR 1.42, 95%CI 0.87, 2.31). The MacDonald study’ therapy showed to be statistically
Secondary Outcome
Side effects and adverse reactions due to therapy was the second outcome being evaluated. Due to the variety of therapies being used, heterogeneity remained a problem in the NAC group. ACRT had the most prevalence for post-operative complications with 49 patients suffering from toxicities which required treatments to stop and an additional 3 who died as a result from the treatment in the MacDonald et al. group 18. In the Sung Kim et al. study 101 patients could not complete ACRT due to
than 10% of the population. These side effects included adhesive ileus, myelosuppression, sepsis, pulmonary fibrosis, intestinal fibrosis, hepatic events, pain, neurologic dysfunction, and cardiac events. The side effects varied between treatments for the NAC. Hartgrink reported 5 patients suffering from toxicity23. Nio recorded a total of 24 patients suffering from anorexia, leukopenia, thrombocytopenia,
liver dysfunction, and massive GI bleeding from carcinoma21. Schuhmacher’s study reported 8 patients
with more mild side effects such as renal toxicity, cardiac toxicity, nausea, vomiting, and diarrhea22. In
contrast, Imano’s study recorded no toxicities25. The overall rate of side effects was 18% across all the
NAC studies. Bias Evaluation
The Cochrane Risk of Bias tool (Appendix D) was used to evaluate each study for individual bias and GRADE (Appendix E) was used to evaluate Bias across outcomes.17,18,21,23–25,27 Allocation and blinding
were previously stated problems across all of the NAC studies17 Nio et al. had a high risk of selection bias
et al. Also, the patients were told of the desired outcomes of each trial, so there is a high risk of detection bias.
Another source of bias was small numbers of patients draw inaccuracy of conclusions on
Hartgrink, Zhao, Schumacher, and Imano17. There were several measurement bias noted throughout the
studies. MacDonald had inclusion criteria for pre-operative major organ functions which were not present in any other study18. This could have affected the overall health of all the patients in the ACRT
study. Every NAC therapy was different. This caused a heterogeneity between that group as a whole. Another source of measurement bias were the varieties of surgeries. Since no specific surgery was tracked, post-operation mortality could be due to an inadequate procedure. Although the NAC did specifically only entail gastric adenocarcinomas, the ACRT studies included gastro-esophageal junction adenocarcinomas as well. This may result in a higher mortality rate along with more severe side effects.
Discussion
The primary outcomes studied in this comparison was the effect on mortality on gastric adenocarcinomas of NAC vs ACRT. No statiscally significant benefit to either therapy could be
determined throught the network meta-analysis. Although ACRT was statistically more beneficial in 5-year and overall survival than surgery alone where NAC was not, the evidence was leaning toward a possibility that NAC may have had a benefit. This observation created the possibility that NAC may be as therapeutic in the survivial benefit as ACRT in the treatment of gastric adenocarcinomas.
There were 2 main measurement biases which could have affected the outcomes of the trials. The first measurement bias noted was the inclusion criteria the ACRT study set for organ function prior to surgery. MacDonald AND Sung Kim made sure their patients had a certain level of health defined as18:
1. creatinine concentration no more than 25 percent higher than the upper limit of normal 2. hemogram within the normal limits
4. serum aspartate aminotransferase concentration no more than five times the upper limit of normal
5. alkaline phosphatase concentration no more than five times the upper limit of normal and this created a consistency in their participants.
The NAC studies had no overall health of organ function criteria prior to initiation of therapy21–25.
This may have created a benefit in 3-year survival for ACRT which would not have existed if all
participants in all of the studies entered with the same criteria. The second measurement bias was the difference in surgeries. D0, D1, and D2 lymphandectomy/gastrectomy were performed throughout the studies. The ACRT trial did not specify which type of gastrectomy was being performed. As previously stated Hartgrink underperformed in the 3-year period, and all the patients underwent a D1
gastrectomy23. This under-performance could then be attributed to the delay in a curative surgery and
causing a further progression of the disease or the ACRT could have used a D2 surgery and had an immediate curative effect. Also, the ACRT study included gastroesophageal junction adenocarcinomas, whereas the NAC studies did not18. This may have increased probability of overall mortality of the
patients in the ACRT group prior to the start of the study. Heterogeniety in the NAC arm was also a contributing factor to the inconclusive data. None of the studies used exactly the same drugs, duration of therapy, or routes of administration; the most common NAC pharmacologic treatment being
Fluorouracil used in 3 of the 7 RCT (see Appendix C). There were noted advantages and disadvantages of each NAC therapy. Hartgrink and Zhao’s therapies had inferior performance in the 3-year comparisons to the other studies23,24. Nio did show improvement over SA, but the improvement was statistically
insignificant21. Imano’s study had the widest variants25. Overall the was no consistent data, or even a
trend of consistent findings, between the NAC studies.
out of 411) compared to the ACRT (244 out of 825) 18,21–25. The surgeries and location of the cancers had
little to do with the adverse reactions to the therapies administered. The overall health of the patients could be considered a bias with an unfair advantage given to the ACRT group, but NAC still out
performed them. The NAC group did use different therapies, and this source of measurement bias may contribute the most to the strength of the evidence. Nio and Schumacher had the highest overall rate of notable toxicities, 23.5% and 32%, respectively, but they are still lower than the rate of toxicity from the MacDonald study (54%) or Sung Kim (34%)18,21,22.
Overall the strength of the evidence is low to any advantage of survivability of a gastric adenocarcinoma with the use of neoadjuvant chemotherapy plus surgery or surgery then adjuvant chemoradiotherapy. There may be a correlation of evidence which reflects that neoadjuvant
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Appendix A Cancer Overview
Table 1 Trends in 5-Year Relative Survival Rates (%) by Race and Year of Diagnosis, United States, 1975 to 2007
All Races Caucasian African American
1975 to 1977 1987 to 1989 2001 to 2007 1975 to 1977 1987 to 1989 2001 to 2007 1975 to 1977 1987 to 1989 2001 to 2007
All cancer 49 56 67 50 57 69 39 43 59
Nervous system 22 29 35 22 28 34 25 31 40
Breast (female) 75 84 90 76 85 91 62 71 77
Colon 51 60 65 51 61 67 45 53 55
Esophagus 5 10 19 6 11 20 3 7 13
Hodgkins Lymphoma 72 79 86 72 80 88 70 72 81
Kidney 50 57 71 50 57 71 49 55 68
Larynx 66 66 63 67 67 65 59 56 52
Leukemia 34 43 57 35 44 57 33 36 50
Liver and bile duct 3 5 15 3 6 15 2 3 10
Lung and bronchus 12 13 16 12 13 17 11 11 13
Melanoma of the skin 82 88 93 82 88 93 58 79 73
Myeloma 25 28 41 25 27 42 30 30 41
Non-Hodgkin Lymphoma 47 51 70 47 52 71 48 46 62
Oral cavity 53 54 63 54 56 65 36 34 45
Ovary 36 38 44 35 38 43 42 34 36
Pancreas 2 4 6 3 3 6 2 6 4
Prostate 68 83 100 69 85 100 61 72 98
Rectum 48 58 68 48 59 69 45 52 61
Stomach 15 20 27 14 19 26 16 19 27
Testicle 83 95 96 83 95 97 73 88 86
Thyroid 92 95 97 92 94 98 90 92 95
Urinary bladder 73 79 80 74 80 81 50 63 64
Uterine cervix 69 70 69 70 73 70 65 57 61
Appendix B Excluded Articles
The following articles were excluded due to use of additional therapies to neoadjuvant chemotherapy: 1. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone
for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20
2. Lowy AM, Feig BW, Janjan N, Rich TA, Pisters PW, Ajani JA, et al. A pilot study of preoperative chemoradiotherapy for resectable gastric cancer. Ann Surg Oncol. 2001 Jul;8(6):519–524. 3. Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PWT, Crane CH, et al. Phase II trial of
preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006 Aug 20;24(24):3953–3958.
4. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJH, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11–20.
The following articles were excluded due to use of only adjuvant chemotherapy without radiation: 1. Bang Y-J, Kim Y-W, Yang H-K, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after
D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379(9813):315–321
2. Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011;29(33):4387–4393
3. The GASTRIC group. Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis.JAMA. 2010;303(17):1729–1737
4. Di Costanzo F, Gasperoni S, Manzione L, et al. Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. J Natl Cancer Inst.
2008;100(6):388–398
5. De Vita F, Giuliani F, Orditura M, et al. Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study). Ann Oncol.
2007;18(8):1354–1358
6. Cirera L, Balil A, Batiste-Alentorn E, et al. Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol. 1999;17(12):3810–3815 7. Bajetta E, Buzzoni R, Mariani L, et al. Adjuvant chemotherapy in gastric cancer: 5-year results of
a randomised study by the Italian Trials in Medical Oncology (ITMO) Group. Ann Oncol. 2002;13(2):299–307
9. Bouché O, Ychou M, Burtin P, et al. Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). Ann Oncol. 2005;16(9):1488–1497
10. Krook JE, O’Connell MJ, Wieand HS, et al. A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer. Cancer. 1991;67(10):2454–2458 [
11. 24. Lise M, Nitti D, Marchet A, et al. Final results of a phase III clinical trial of adjuvant
chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer. J Clin Oncol. 1995;13(11):2757–2763
12. Macdonald JS, Fleming TR, Peterson RF, et al. Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: a Southwest Oncology Group study. Ann Surg Oncol. 1995;2(6):488–494 13. Nakajima T, Kinoshita T, Nashimoto A, et al. Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer. Br J Surg. 2007;94(12):1468–1476
14. Nakajima T, Nashimoto A, Kitamura M, et al. Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Gastric Cancer Surgical Study Group. Lancet. 1999;354(9175):273–277
15. Nashimoto A, Nakajima T, Furukawa H, et al. Randomized trial of adjuvant chemotherapy with mitomycin, fluorouracil, and cytosine arabinoside followed by oral fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology Group 9206-1. J Clin Oncol. 2003;21(12):2282– 2287
16. Nitti D, Wils J, Dos Santos JG, et al. Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG. Ann Oncol. 2006;17(2):262–269
The following articles were excluded due to unclear documentation of a D1/D2 surgery:
1. Tsavaris NB, Tentas K, Kosmidis P, et al. Fluorouracil, epirubicin, and mitomycin C versus 5-fluorouracil, epirubicin, mitomycin C, and leucovorin in advanced gastric carcinoma. A randomized trial. Am J Clin Oncol. 1996;19(5):517–521
2. Yonemura Y, Sawa T, Kinoshita K, Matsuki N, Fushida S, Tanaka S, et al. Neoadjuvant
chemotherapy for high-grade advanced gastric cancer. World J Surg. 1993 Mar;17(2):256–261.
The following articles were excluded due to the abstracts being written in English, but the random controlled trials were only available in Japanese:
1. Lowy AM, Mansfield PF, Leach SD, Pazdur R, Dumas P, Ajani JA. Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer. Ann Surg. 1999 Mar;229(3):303–308.
3. Masuyama M, Taniguchi H, Takeuchi K, Miyata K, Koyama H, Tanaka H, et al. [Recurrence and survival rate of advanced gastric cancer after preoperative EAP-II intra-arterial infusion therapy]. Gan To Kagaku Ryoho. 1994 Sep;21(13):2253–2255.
Appendix C
Demographics and Therapies Study Demographics
NAC ACRT
Hartgrink Nio Zhao Imano Schumacher Wang Kobayashi MacDonald Sung Kim
N 29 102 40 47 72 30 91 281 544
Age (yrs)
Median na 64 57.5 60 56 54 na 60 54
Range up to 75 51-75 32-70 46-72 38-70 37-65 up to 75 25-87 23-70
Male sex % na 70 69 69 69.4 76.7 na 72 65.5
T stage
T1 or T2 15 62 na 22 0 19 na 31 52.4
T3 4 15 na 25 68 11 na 62 44.3
T4 8 25 na 0 4 0 na 6 3.3
Location of primary tumor
Antrum 14 na na 6 na na na 53 261
Corpus 15 na na 8 na na na 24 227
Cardia 0 na na 28 na na na 21 48
Multicentric 0 na na 5 na na na 2 9
Thearpies During the Trials
Neoadjuvant Chemotherapy
PO Tegafur/uracil 7 mg/kg/d×21 d
DDP (50 mg/m2/d×3 d), d-L-folinic acid (500 mg/m2/d×6 d), 5-FU (2000 mg/m2/d×6 d); 2 courses; intravenous IV methotrexate 1500 mg/m2 plus IV Fluorouracil 1500 mg/m2 plus leucovorin 30 mg/6 h×2 d plus doxorubicin 30 mg/m2 for 4 courses
PO doxifluridine 800–1200 mg/d or
IV 500mg Fluorouracil plus Cisplatin/Fluorouracil 200 mg/d ×3–5 d IV Fluorouracil 330 mg/m2/d×3 d
or
IV Cisplatin 18 mg/m2 x 3d or
IV Cisplatin/Fluorouracil 200 mg/d ×3
PO Flourouracil 2x20ml/day, over 12.5 days, total dosing being 2g, oleic acid, ginseng polysaccharides, bean phosopholipids, and cholesterol
PO doxifluridine 610 mg/m2/d 6 10 d
Adjuvant Chemoradiotherapy
400 mg/m2 of fluorouracil plus 20 mg/m2 of leucovorin for 5 days, followed by 4,500 cGy of radiotherapy for 5 weeks, with fluorouracil and leucovorin on the first 4 and the last 3 days of radiotherapy. Two 5-day cycles of fluorouracil and leucovorin were given 4 weeks after the completion of radiotherapy. The dose of fluorouracil was reduced in patients who had grade 3 or 4 toxic effects.
400 mg/m2 of fluorouracil plus 20 mg/m2 of leucovorin for 5 days, followed by 4,500 cGy of radiotherapy for 5 weeks, with fluorouracil and leucovorin on the first 4 and the last 3 days of radiotherapy. Two 5-day cycles of fluorouracil and leucovorin were given 4 weeks after the completion of radiotherapy.
Appendix D Cochrane Risk of Bias Random Sequence
Generation
Allocation of
Concealment Selective Reporting Other Bias
Blinding of Participants and Personnel
Blinding of Outcome Assessment
Incomplete Outcome Data
Nio - - + + - ? +
Schumacher + + + ? + + +
Hartgrink + - + + + + +
Zhao ? + + + + + +
Imano + + + + + + +
Wang + ? + + - + +
Kobayashi + + + + ? + +
MacDonald ? ? + - ? ? +
Sung Kim ? ? + - ? ? +
Key
Appendix E GRADE
Question:
No of studies Design Limitations Inconsistencies Indirectness Imprecision ConsiderationsOther NAC Surgery Alone Relative Risk(95% CI) Absolute
NAC's were not
the same Post operative illness confounding
Surgeries were not the same Inclusion criteria of patients were not the same
NAC's were not
the same Post operative illness confounding
Surgeries were not the same Inclusion criteria of patients were not the same
NAC's were not the same
Post operative illness confounding
Surgeries were not the same
Inclusion criteria of patients were not the same
2/5 Critical
Surgical complication confounding All Purpose Mortality (# of deaths/participants)- NAC
7 randomized trials
Participants due to side effects of
the therapies direct
Staging of cancers before
the study was done from
different literature
175/411 191/441 0.93 (0.81, 1.08)
40 per 1000 people benefit from NAC over Surgery Alone 246/421 1.02 (0.91, 1.15)
17 per 1000 people benefit from NAC over Surgery Alone 2/5 Critical Surgical complication confounding 2/5 Critical Surgical complication confounding
5-Year Survivability- NAC
7 randomized trials to side effects of Participants due the therapies
direct
Staging of cancers before
the study was done from
different literature
208/371 3-Year Survivability- NAC
7 randomized trials to side effects of Participants due the therapies
direct
Staging of cancers before
the study was done from
different literature
179/290 212/331 1.05 (0.91, 1.22)
26 per 1000 people benefit from NAC over Surgery Alone
How necessary is neoadjuvant chemotherapy in addition to surgery compared to surgery then adjuvant chemoradiotherapy in improvement of 5-year survivability of a gastric adenocarcinoma?
Quality Assessment Summary of Finding
Importance No of Patients Effect
Quality
Question:
No of studies Design Limitations Inconsistencies Indirectness Imprecision ConsiderationsOther ACRT Surgery Alone Relative Risk(95% CI) Absolute
Post operative illness confounding
Post operative illness confounding
Post operative illness confounding
How necessary is neoadjuvant chemotherapy in addition to surgery compared to surgery then adjuvant chemoradiotherapy in improvement of 5-year survivability of a gastric adenocarcinoma?
Quality Assessment Summary of Finding
Importance No of Patients Effect
Quality
3-Year Survivability- ACRT
2 randomized trials to side effects of Participants due the therapies
direct None 511/825 381/721 1.15 (1.06, 1.25)
83 per 1000 people benefit from ACRT over Surgery Alone Critical Surgical complication confounding
5-Year Survivability- ACRT
2 randomized trials to side effects of Participants due the therapies
direct None 426/825
4/5 Critical
Surgical complication confounding 2 randomized trials to side effects of Participants due
the therapies
direct None 400/825
Surgeries were not the same
Surgeries were not the same
Surgeries were not the same All Purpose Mortality (# of deaths/participants)- ACRT
436/721 0.81 (0.71, 0.92)
130 per 1000 people benefit from
ACRT over Surgery
Alone
288/721 1.42 (0.87, 2.31)
Appendix F
